|Year : 2021 | Volume
| Issue : 1 | Page : 14-17
Is the nature (extent and characteristics) of schistosoma-induced chronic inflammation organ dependents?
Shamsu Sahalu Bello1, Akinfenwa Taoheed Atanda2, OA O. Olatunde1, SL Gana1, AB Ibrahim-Saad1
1 Department of Histopathology, Aminu Kano Teaching Hospital, Kano, Nigeria
2 Department of Histopathology, Aminu Kano Teaching Hospital; Department of Histopathology, Bayero University Kano, Kano, Nigeria
|Date of Submission||23-Sep-2020|
|Date of Decision||13-Dec-2020|
|Date of Acceptance||31-Dec-2020|
|Date of Web Publication||4-May-2021|
Dr. Shamsu Sahalu Bello
Department of Pathology, Aminu Kano Teaching Hospital, PMB 3452, Kano
Source of Support: None, Conflict of Interest: None
Context: Pathogenesis of schistosomiasis related bladder cancer has been attributed to induced chronic inflammation and its sequelae. There is paucity of studies on the inflammatory cell profile. Aim: This study, therefore, aims to characterise the degree and repertoire of this inflammatory response. Settings and Design: A retrospective study of all non-neoplastic cases of schistosomiasis histologically confirmed between January 2012 and December 2019 in a tertiary hospital. Materials and Methods: Data were retrieved from archives and slides made for the cases were evaluated for ova density, type and degree of inflammation and pattern of fibrosis. Statistical Analysis: The degree of inter observer variation (kappa value) was also calculated while statistical significance was set at P ≤ 0.5 at 95% confidence interval. Results: Eighty one cases were diagnosed in the study period. The mean age was 33.8 years and M:F ratio was 15:1. Bladder, ureter, gastrointestinal tract, testes and other less frequent sites accounted for 58.0%, 12.0%, 8.0%, 8.0% and 7.4% of cases, respectively. Eosinophilic infiltration and granulomatous reaction were predominantly minimal even in cases with significant oviposition. There was no significant difference between ova density and degree of overall inflammation (P = 0.9) or between ova density and degree of lymphocytic infiltration (P = 0.2). Similarly, even though fibrosis was more frequent in cases with high ova density, no significant difference was found in cases with low ova density. Conclusion: Even though carcinogenesis in bladder schistosomiasis has been attributed to chronic inflammation and fibrosis, this study, however, showed that there are no statistically significant differences between schistosoma ova density and degree of inflammation as well as fibrosis in both bladder and other organs.
Keywords: Bladder, chronic inflammation, fibrosis, schistosomiasis, ureter
|How to cite this article:|
Bello SS, Atanda AT, O. Olatunde O A, Gana S L, Ibrahim-Saad A B. Is the nature (extent and characteristics) of schistosoma-induced chronic inflammation organ dependents?. Niger J Basic Clin Sci 2021;18:14-7
|How to cite this URL:|
Bello SS, Atanda AT, O. Olatunde O A, Gana S L, Ibrahim-Saad A B. Is the nature (extent and characteristics) of schistosoma-induced chronic inflammation organ dependents?. Niger J Basic Clin Sci [serial online] 2021 [cited 2021 Jun 23];18:14-7. Available from: https://www.njbcs.net/text.asp?2021/18/1/14/315409
| Introduction|| |
Schistosomiasis, one of the neglected tropical diseases, affects over 200 million individuals worldwide and has a pooled prevalence of 34.7% in Nigeria., While its association with bladder cancer is indubitable, controversies abound with respect to the pathogenesis. One of the most widely accepted pathogenetic mechanisms is the chronic inflammatory response against schistosoma ova. This has been postulated to induce the generation of genotoxic free radicals which are potent inducers of chromosomal aberrations that have characterised cancer. Some studies reported that opposing action between type 2 T-helper cells and regulatory T-cells are responsible for tissue pathology,, whereas others documented no correlation between schistosma ova density and degree of inflammation at various sites of the body. Yet, the inflammatory profile of these cases has scarcely been studied.
The aim of this study, therefore, is to characterise the degree and profile of this inflammatory response to better understand their potential roles in schistosoma-induced bladder cancer.
| Materials and Methods|| |
Laboratory records and corresponding stained slides of all non-neoplastic cases diagnosed with schistosomiasis between January 2012 and December 2019 in a teaching hospital in northern Nigeria were retrieved from archives. Data extracted from the digital records included age and gender and site of biopsy.
The slides were evaluated for schistosoma ova density which was assessed as the average number of ova in high power fields (diameter 0.65 mm) across the longest axis of the slide. Using a cut-off of 10 (median of 11 reported by Randrianasolo et al.) the cases were scored as low density (0–5), moderate density (6–10) and high density (>10).
Overall degrees of inflammation including lymphocytic, neutrophilic, plasmacytic and eosinophilic densities were also evaluated using an adapted model developed by Klintrup et al. where the absence of inflammatory cells was scored 0; 1 was assigned to mild and patchy inflammation, 2 for moderate inflammation up to 1 high power field from the ova, and 3 for very intense inflammatory reaction around the ova.
Granulomatous inflammation was scored as present or absent, and fibrosis was also rated as present or absent.
The degree of inter-observer variation (kappa value) was also calculated while statistical significance was set at P ≤ 0.5 at 95% confidence interval.
| Results|| |
In the study period between January 2012 and December 2019 there were a total of 81 histologically confirmed cases of schistosomiasis not related to cancer. The patients are aged between 8 and 90 years with the average age of 33.8 years. Of the 81 cases, 76 (93.8%) were males, while 5 (6.2%) were females giving M:F ratio of 15:1, as shown on [Figure 1].
As shown in [Table 1], bladder schistosomiasis predominated with 47 (58.0%) cases, followed in frequency by ureteric involvement seen in 12 (14.8%) cases, whereas other sites accounting for 6 (7.4%) of the cases included the female genital tract, prostate, peritoneum and skin.
Correlation of ova density, degree of inflammation and degree of fibrosis in the different organs as shown in [Table 2] reveals consistency in these 3 parameters in the bladder and ureter. These consisted of high ova density (46.8%) as depicted in [Figure 2] being associated with the higher frequency of significant inflammation (59.6%) and higher frequency of fibrosis (89.4%). A similar pattern was observed in ureteric cases. In testicular, GIT and other cases, ova deposition was minimal to moderate and correspondingly, inflammation was also minimal. Predominantly T-lymphocytes and to a lesser degree B-lymphocytes were observed to constitute the lymphocytic infiltrates as shown in [Figure 3]. However, fibrosis was significant irrespective of degrees of ova deposition or inflammation. [Figure 4] illustrates the presence of fibrosis in bladder tissue using the Masson Trichrome stain.
|Table 2: Pattern of ova density, inflammation and fibrosis in the different organs affected|
Click here to view
|Figure 2: (a) Slides show schistosoma ova density in bladder tissue (H and E, ×10). (b) Slides show schistosoma ova density in bladder tissue (H and E, ×40)|
Click here to view
|Figure 3: (a) Smaller percentage of the lymphocytic infiltrates staining for B-cell marker (CD20) and (b) the larger percentage of the lymphocytic infiltrates are positive for T-cell marker (CD3) (×40)|
Click here to view
|Figure 4: Schistosoma ova surrounded by fibrotic stroma. Mason's Trichrome ×40|
Click here to view
With respect to the relationship between inflammation and fibrosis and ova density, as shown in [Table 2], there were no statistically significant differences between ova density and degree of overall inflammation (P = 0.9) or between ova density and degree of lymphocytic infiltration (P = 0.2). Even though eosinophiliic infiltration was predominantly minimal even in cases with significant ova deposition, it, however, showed no statistically significant correlation with ova density. Similarly, even though fibrosis was more frequent in cases with high ova density, this did not also show any statistically significant difference compared to those with low ova density As depicted in [Table 3].
Kappa value of 0.47 corresponding to 'moderate' for inter-observer variability was found.
| Discussion|| |
The predominance of male subjects among the cases, as found in this study, is in consonance with earlier reports from the region by Dawaki et al. Our study, however, differs from theirs with respect to their reported mean age of 25 years compared to the 33.8 years found in ours. With primary infection in the first to second decades of life and a parasite that lives for an average of 3–10 years, this may explain the greater likelihood of presentation with chronic complications requiring biopsy, as reflected in our older mean age. The younger mean age of our testicular cases reflects both accessibilities of the organ and earlier presentation.
Histologically, in all the organs studied, only about 15% of our cases showed significant eosinophil infiltrates around the parasite ova and accompanying stroma. Studies have shown that eosinophil response is more robust against larval (intermediate) stages of parasites. This is typified by the Katayama syndrome characterised by penetration of cercaria into the bloodstream and eosinophilia among other symptoms. In chronic phases, as exemplified by our findings, there is the predominance of T-lymphocytic infiltrates [Figure 3] with switch to a T-helper type 2 (Th2) inflammatory repertoire. This stage is also characterised by a reduction in granulomatous reaction and a preponderance of fibrosis [Figure 4]. This is also corroborated by the findings of this study where the granulomatous reaction was found in only 24.7% of cases.
Fibrosis has been recognised as playing a significant role in carcinogenesis. The fibroblasts in the inflammatory milieu produce a host of cytokines, including transforming growth factor-β, tumour necrosis factor α and alpha-smooth muscle actin among others. These have been associated with abnormal cell-matrix communication with subsequent carcinogenesis, epithelial-mesenchymal transition and metastasis.
Although fibrosis was present in 71 (87.7%) of the 81 cases, there was however, no statistically significant correlation with the degree of accompanying inflammation (P = 0.15) or degree of oviposition in any of the organs studied (P = 0.8). This then raises the question: if carcinogenesis associated with bladder schistosomiasis is attributed to chronic inflammation and fibrosis,, why then is there paucity of schistosomiasis-associated carcinogenesis in the other affected organs which show similar pattern of inflammation and fibrosis to oviposition?; especially the ureter which has similar epithelial lining and is the tissue most commonly affected by the parasite after the bladder. In the centre where this study was conducted the ratio of ureteric to bladder schistosomiasis is approximately 1:6 and of 59 ureteric carcinomas diagnosed in the period between 1999 and 2019 none of them was associated with schistosomiasis.
While case reports and occasional studies have related schistosomiasis with carcinogenesis in other organs, these have not clearly shown cause-effect relationships and this may explain why, even though Schistosoma haematobium has merited a category 1 designation, it is only for bladder cancer. Could there be factors present in the schistosoma – infested bladder that predisposes it to carcinogenesis but which is not present in other organs, even though they exhibit similar tissue response to the infection? Soluble egg antigens, oestrogen-like metabolites, guanine-derived oxidation products and the haematobium interleukin-4 inducing principle of Shistosoma eggs have all been studied and identified to play roles in schistosoma-associated bladder cancer. However, yet, no evidences exist showing these are also not produced at other extra-vesical sites of infestation.
A candidate factor that may explain the foregoing has to be an extra-parasite factor which would be present almost exclusively in the bladder millieu and absent at other sites. Such candidate factors may be in the content of the bladder, that is, urine, or the bladder epithelium itself. With regards to the latter, Nacif-Pimenta et al. showed that the effect of Schistosoma ova on cell proliferation may depend solely on the cell type. This was evidenced by the finding that Schistosoma ova promoted proliferation of urothelial cells but inhibited the growth of cholangiocytes. While this may not completely explain the paucity of schistosomiasis-related carcinogenesis in other organs, the role of bacterial infection, by itself or as a co-factor has also been explored.
In contrast to the bladder, which may readily harbour bacterial infections, other sites are relatively more sterile and less readily infected. Similarly, exposure of urinary tract mucosa to nitoroamines, well-documented carcinogens, are also more likely to be found in the bladder than other sites. Interestingly, the experimental study by El-Mosalamy et al. showed that the synergistic relationship between Escherichia coli and nitrosoamines compared to other experimental groups gave the most significant bladder lesions. Martin et al., conducted a systematic review focusing on risk factors of schistosoma-associated and non-schistosoma-associated squamous cell carcinoma of the bladder and highlighted the role of urinary tract infection as a common aetiologic risk factor in both.
| Conclusion|| |
In summary, in all the organs histologically examined in this study, paucity of eosinophils and granulomatous reaction, presence of lymphocytic infiltration and fibrosis are common factors. Yet with clinical records in the study centre showed rare schistosoma-associated malignancy in these organs other than the bladder., As such other factors not studied in this research may contribute to carcinogenesis.
Most of the bladder biopsies examined in this study were obtained cystoscopically, thus limiting the extent of overall evaluation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
McAdam AJ, Milner DA, Sharpe AH. Infectious disease. In: Kumar V, Abbas AK, Aster JC, editors. Robins and Cotran. Pathologic basis of Disease. 9th
ed. Philadelphia: Saunders Elsevier; 2015. p. 397-8.
Abdulkadir A, Ahmed M, Abubakar BM, Suleiman IE, Yusuf I, Imam IM, et al
. Prevalence of urinary schistosomiasis in Nigeria, 1994–2015: Systematic review and meta-analysis. Afr J Urol 2017;23:228-39.
Barsoum RS, Esmat G, El-Baz T. Human schistosomiasis: Clinical perspective: Review. J Adv Res 2013;4:433-44.
Nweke CP, Shiff CJ, Okudo JC. The etiological association between Schistosoma hematobium infestation and bladder cancer in Africa and the Middle East. Peak J Public Health Manag 2015;3:10-7.
Burke ML, Jones MK, Gobert GN, Li YS, Ellis MK, McManus DP. Immunopathogenesis of human schistosomiasis. Parasite Immunol 2009;31:163-76.
Baumgart M, Tompkins F, Leng J, Hesse M. Naturally occurring CD4+Foxp3+regulatory T cells are an essential, IL-10-independent part of the immunoregulatory network in Schistosoma mansoni egg-induced inflammation. J Immunol 2006;176:5374-87.
Gelfand M, Ross CM, Blair DM, Castle WM, Weber MC. Schistosomiasis of the male pelvic organs. Severity of infection as determined by digestion of tissue and histologic methods in 300 cadavers. Am J Trop Med Hyg 1970;19:779-84.
Randrianasolo BS, Jourdan PM, Ravoniarimbinina P, Ramarokoto CE, Rakotomanana F, Ravaoalimalala VE, et al
. Gynecological manifestations, histopathological findings, and schistosoma-specific polymerase chain reaction results among women with Schistosoma haematobium infection: A cross-sectional study in Madagascar. J Infect Dis 2015;212:275-84.
Klintrup K, Mäkinen JM, Kauppila S, Väre PO, Melkko J, Tuominen H, et al
. Inflammation and prognosis in colorectal cancer. Eur J Cancer 2005;41:2645-54.
Dawaki S, Al-Mekhlafi HM, Ithoi I, Ibrahim J, Abdulsalam AM, Ahmed A, et al
. The menace of schistosomiasis in Nigeria: Knowledge, attitude, and practices regarding schistosomiasis among rural communities in Kano State. PLoS One 2015;10:e0143667.
Klion AD, Nutman TB. The role of eosinophils in host defense against helminth parasites. J Allergy Clin Immunol 2004;113:30-7.
Brücher BL, Jamall IS. Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation. 4open 2019;2:11.
Michaud DS. Chronic inflammation and bladder cancer. Urol Oncol 2007;25:260-8.
Sui X, Lei L, Chen L, Xie T, Li X. Inflammatory microenvironment in the initiation and progression of bladder cancer. Oncotarget 2017;8:93279-94.
Ishida K, Hsieh MH. Understanding urogenital schistosomiasis-related bladder cancer: An update. Front Med (Lausanne) 2018;5:223.
Nacif-Pimenta R, da Silva Orfanó A, Mosley IA, Karinshak SE, Ishida K, Mann VH, et al
. Differential responses of epithelial cells from urinary and biliary tract to eggs of Schistosoma haematobium
and S. mansoni
. Sci Rep 2019;9:10731.
El-Mosalamy H, Salman TM, Ashmawey AM, Osama N. Role of chronic Escherichia coli
infection in the process of bladder cancer – An experimental study. Infect Agent Cancer 2012;7:19.
Martin JW, Carballido EM, Ahmed A, Farhan B, Dutta R, Smith C, et al
. Squamous cell carcinoma of the urinary bladder: Systematic review of clinical characteristics and therapeutic approaches. Arab J Urol 2016;14:183-91.
Ochicha O, Alhassan S, Mohammed AZ, Edino ST, Nwokedi EE. Bladder cancer in Kano – A histopathological review. West Afr J Med 2003;22:202-4.
Akarken İ, Dere Y. Could trop-2 overexpression indicate tumor aggressiveness among prostatic adenocarcinomas? Ann Diagn Pathol 2020;50:151680.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]